A syndrome of fat redistribution and metabolic abnormalities is being reported with increasing frequency in persons with HIV infection, most often in association with the class of antiretroviral drug, protease inhibitors. Common manifestations include abdominal obesity, thinning of the extremities, dorsocervical fat accumulation, insulin resistance, and dyslipidemias. The etiology, mechanism, and treatment of this syndrome are unclear. Given the tremendous improvements in morbidity and mortality seen with protease inhibitors (PIs), and the risk of viral resistance, discontinuation of these medications is currently not appropriate management for fat distribution of the accompanying metabolic abnormalities. Although the short-term outlook for HIV disease has greatly improved, the cardiovascular consequences of abdominal obesity, insulin resistance, and lipid abnormalities are well-established in HIV-seronegative populations. The long-term objectives of this project are: to clarify the role of PIs and other highly-active antiretroviral therapy (HAART) regimens in causing the syndrome; to recognize non-pharmacologic pre-disposing factors; to understand the course of the syndrome's development; and to test a possible treatment for abdominal adiposity. This project includes: a) analyses of relevant data collected from the NFL cohort; b) a metabolically more intensive cohort study of 50 persons not currently taking PIs, 25 of whom are planning to start PIs; and c) a randomized clinical trial of the management of insulin resistance with diet and metformin hydrochloride (1.5 g/day) for 6 months in 50 persons with HAART-associated abdominal obesity.